Medicine (RMH) - Theses
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ItemInvestigation of the synergy between Alzheimer’s Disease and epilepsy through data-driven molecular networks( 2023-03)Overview: In the recent years, a bi-directional association between Alzheimer’s Disease (AD) and epilepsy has been observed, with AD-like cognitive impairments often presenting in epilepsy patients, and high rates of epileptic seizures seen in a sub-set of AD patients. These seizure-prone AD patients reportedly show accelerated cognitive decline and more aggressive disease progression compared to those without seizures. The mechanism and primary mode of action of this association remains unknown, although a synergistic interaction has been proposed. The general aim of this doctoral research was to investigate the electrical and molecular properties of the above-mentioned pathophenotypes and elucidate the mechanisms underlying the potential synergy between AD-like amyloid pathology and epileptiform activity, and their role in accelerated cognitive decline. Introduction and literature review: The introductory sections of Chapter 1 provide an overview of the current literature on epilepsy and Alzheimer’s Disease, focusing on pathophysiological mechanisms commonly implicated in both syndromes. The subsequent sections discuss several benchmark studies that first reported on the increased co-occurrence of seizures among AD patients, followed by a critical review of the most prominent as well as recently emerged hypotheses that aim to provide mechanistic insight into the nature of the proposed bi-directional association between AD and acquired epilepsy. The concluding sections provide a gentle introduction into the emerging field of network medicine, systems- based analysis, interrogation methods of high-throughput biological data and the general framework of computational models and methodology that was implemented throughout this work. Experimental chapters: The first and second experimental chapters aim to characterize the molecular signature of a brain affected by amyloid pathology and seizures. Utilizing proteomic and metabolomic data from two collaborative studies as well as publicly available transcriptomic data, Chapter 2 describes the molecular signature of human AD and that of most widely used mouse models of AD, while Chapter 3 captures the molecular profile of well- established rat models of genetic (GAERS) and acquired (post SE) epilepsies. Informed by the insight gained from Chapters 2 and 3, the third experimental chapter (Chapter 4) aimed to capture the shared molecular signature associated with AD and temporal lobe epilepsy (TLE) – the most common type of epilepsy comorbid with AD. A hypothesis-free, systems-level approach was used to characterize the pathophysiological state of each disease on a molecular level by constructing data-driven gene coexpression networks representing the respective pathologies. The topology and architecture as well as the preservation of functional gene modules between the two networks were compared through network preservation analysis, identifying two clusters of synaptic reorganization and signalling-associated genes as highly preserved between AD and TLE. The fourth and final experimental chapter (Chapter 5) aims to investigate the mechanism and potential mediators of the bi-directional relationship between amyloid pathology and epilepsy by examining the effect of recurrent seizures on hallmark features of AD pathology such as amyloid plaque deposition and cognitive performance. RNA sequencing and bioinformatic analysis of mouse hippocampal tissue was conducted in order to investigate the molecular mechanisms of synergy between recurrent seizures and already- present AD pathology as well as identify key mediators of accelerated disease progression, which could serve as promising targets for intervention. Discussion and conclusions: Informed by computational analysis from chapters 2, 3 and 4, and reinforced by experimental evidence from chapter 5, the final chapter of this thesis (Chapter 6) provides a synthesis of the newly gained insights into the strong synergistic nature of the relationship between amyloid pathology and recurrent seizures. A subsequent extensive review of the most current molecular neuroscience research facilitated interpretation of our results, leading to the proposal of a “dual-pathology” disease model for epilepsy and AD. In this paradigm, the synergistic self-propagating interaction between epileptiform activity and amyloid pathology defines a distinct subpopulation of “dual-pathology” patients, characterized by faster disease progression and more severe cognitive decline. Furthermore, I describe specific cellular pathways mediating the synergy between amyloid pathology and recurrent seizure activity and introduce a mechanistic framework underlying the chain of events through which this synergy leads to accelerated cognitive deterioration. Each step in this framework or chain of events is reinforced by a benchmark proof-of-concept study published in leading peer- reviewed journals and which, with the exception of the most recent 2022-2023 studies, have been independently replicated by other research groups. The concluding sections of this chapter emphasize the utility of integrating phenotypic and electroencephalographic data from in vivo studies with high-throughput “omics” data into network-based computational models for a holistic examination of pathophysiological mechanisms underlying complex diseases and identification of novel therapeutic targets.